Angiogenesis, Cardiac Hypertrophy and Surgical Ischemia

血管生成、心脏肥大和手术缺血

• 批准号: 6893384
• 负责人: Pedro J. del Nido
• 金额: $ 37.95万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6893384
• 关键词: angiogenesis; capillary; cardiac myocytes; cardiovascular surgery; cell growth regulation; congenital heart disorder; disease /disorder model; gene expression; heart failure; hypertrophic myocardiopathy; hypoxia inducible factor 1; intracardiac pressure; intracardiac volume; laboratory rabbit; mitochondria; myocardial ischemia /hypoxia; newborn animals; pathologic process; protein structure function

DESCRIPTION (provided by applicant): In infants and children with congenital heart defects, myocardial hypertrophy in response to chronic pressure or volume overload remains one of the most common causes of heart failure. Despite surgical advances, a chronic high workload state is a common problem seen in management of congenital heart defects and often results in contractile dysfunction and poor tolerance to ischemia imposed by cardiac surgery. To further investigate mechanisms responsible for progression of compensated hypertrophy to decompensated with ventricular dilatation and failure, we have developed a model of pressure-overload hypertrophy from aortic banding of rabbits at 10 days of age, where ventricular hypertrophy progresses from compensated to severe hypertrophy, followed by ventricular dilatation and failure over a 7-8 week period. Concomitant with these changes there is a decline in microvascular density in severe hypertrophy, with impaired substrate delivery and mitochondrial oxidative capacity. We hypothesize that in pressure-overload hypertrophy, the stimulus for myocyte hypertrophy does not result in a concomitant trigger for capillary growth leading to an imbalance of substrate demand to supply. Furthermore, we postulate that activity of hypoxia inducible factor (HIF), the main regulator of adaptive changes to hypoxia in tissues, decreases as hypertrophy progresses to failure. We also postulate that interventions that activate/upregulate HIF will promote capillary growth in pressure-overload hypertrophy and will maintain the normal balance between substrate supply and demand. To test this hypothesis we will pursue two interrelated aims: aim i. determine the activity/expression of hif-1 o_in hypertrophied heart and effects of therapeutic hif activation/upregulation on microvascular density. aim ii - determine the role of mitochondrial dysfunction in regulation of hif- 1a signaling in the hypertrophied myocardium. these studies will provide an improved understanding of the mechanism responsible for the development of heart failure in pressure-overload hypertrophy and will evaluate therapeutic strategies to prevent the onset of failure and improve tolerance to ischemia in hypertrophied myocardium.

描述（由申请人提供）： 在患有先天性心脏病的婴儿和儿童中，慢性压力或容量超负荷引起的心肌肥大仍然是心力衰竭的最常见原因之一。尽管外科手术取得了进展，但慢性高工作负荷状态是先天性心脏病治疗中常见的问题，通常会导致收缩功能障碍和对心脏手术造成的缺血耐受性差。为了进一步研究代偿性肥大进展到失代偿性心室扩张和衰竭的机制，我们通过10天龄兔的主动脉束带建立了压力超负荷肥大模型，其中心室肥大从代偿性肥大进展到严重肥大，随后是心室扩张和心室衰竭，持续7-8周。伴随着这些变化，在重度肥大中微血管密度下降，底物递送和线粒体氧化能力受损。我们假设，在压力超负荷性肥大，刺激心肌细胞肥大不会导致伴随触发毛细血管生长，导致底物的需求供应失衡。此外，我们推测，缺氧诱导因子（HIF）的活性，缺氧的适应性变化的主要调节组织中，随着肥大进展到失败而下降。我们还假设激活/上调HIF的干预措施将促进压力超负荷肥大中的毛细血管生长，并维持底物供应和需求之间的正常平衡。为了检验这一假设，我们将追求两个相互关联的目标：目标i。确定肥厚心脏中HIF-1 α的活性/表达以及治疗性HIF活化/上调对微血管密度的影响。目的II -确定线粒体功能障碍在肥大心肌中调节HIF- 1a信号传导中的作用。这些研究将使人们更好地了解压力超负荷性心肌肥厚导致心力衰竭的机制，并将评价预防心力衰竭发作和提高肥厚心肌对缺血耐受性的治疗策略。